Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Methods
2.1. Patients and Design of the Precision Medicine Platform
2.2. Tissue Samples
2.3. Cancer Gene Panel Sequencing
2.4. Immunohistochemistry (IHC)
2.5. FISH
2.6. Multidisciplinary Team (MDT) for Precision Medicine
2.7. Study Design and Statistics
3. Results
3.1. Patient Characteristics
3.2. Molecular Profile
3.3. Therapy Recommendations and Outcome
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patient Characteristics | Number |
---|---|
Median (range) age in years at first diagnosis | 56.4 (17.7–76.9) |
Median (range) age in years at molecular profiling | 60.6 (19.3–80.3) |
Female patients | 44 (62.0%) |
Male patients | 27 (38.0%) |
Caucasian | 71 (100%) |
Relapsed cancer | 45 |
Metastatic cancer | 71 (100%) |
Systemic anticancer treatment received | 71 (100%) |
Prior lines of systemic anticancer treatment | 2–7 |
mTORC1-inhibitor-based therapy applied: • in female patients; • in male patients. | 23 (32.4%) |
16 (22.5%) | |
7 (9.9%) | |
Tumor entities | |
Gynecologic malignancies | 30 (42.3%) |
Colorectal cancer | 7 (9.9%) |
Head and neck squamous cell carcinomas | 6 (8.5%) |
T-cell lymphoblastic lymphoma | 2 (2.8%) |
Prostate cancer | 3 (4.2%) |
Pancreatic ductal adenocarcinoma | 2 (3.8%) |
Tumors of the central nervous system | 2 (3.8%) |
Biliary tract cancer | 3 (4.2%) |
Fibrolamellar hepatocellular carcinoma | 2 (3.8%) |
Cancer of unknown primary | 2 (3.8%) |
Gastroesophageal junction cancer | 3 (4.2%) |
Non-small-cell lung carcinoma | 4 (5.6%) |
Neuroendocrine neoplasms | 5 (7.0%) |
Mutations detected relevant to the PI3K/Akt/mTOR signaling pathway | |
PTEN | 15 |
PIK3CA | 4 |
STK11 | 3 |
AKT1 | 2 |
MTOR | 0 |
TSC1 | 0 |
TSC2 | 0 |
Total number of mutations detected | 110 |
Mutated Genes | Number of Mutations | Percentage of Occurrence in Patients (n = 71) | Percentage of All Mutations (n = 110) |
---|---|---|---|
TP53 | 34 | 47.9 | 30.9 |
PTEN | 15 | 21.1 | 13.6 |
KRAS | 13 | 18.3 | 11.8 |
APC | 4 | 5.6 | 3.6 |
BRAF | 4 | 5.6 | 3.6 |
KIT | 4 | 5.6 | 3.6 |
PIK3CA | 4 | 5.6 | 3.6 |
ARID1A | 3 | 4.2 | 2.7 |
CTNNB1 | 3 | 4.2 | 2.7 |
IDH1 | 3 | 4.2 | 2.7 |
STK11 | 3 | 4.2 | 2.7 |
AKT1 | 2 | 2.8 | 1.8 |
BRCA2 | 2 | 2.8 | 1.8 |
NF1 | 2 | 2.8 | 1.8 |
NRAS | 2 | 2.8 | 1.8 |
ATM | 1 | 1.4 | 0.9 |
ATR | 1 | 1.4 | 0.9 |
ATRX | 1 | 1.4 | 0.9 |
CHD1 | 1 | 1.4 | 0.9 |
CDKN2A | 1 | 1.4 | 0.9 |
EGFR | 1 | 1.4 | 0.9 |
ERBB2 | 1 | 1.4 | 0.9 |
PIK3R1 | 1 | 1.4 | 0.9 |
PTPN11 | 1 | 1.4 | 0.9 |
RB1 | 1 | 1.4 | 0.9 |
RET | 1 | 1.4 | 0.9 |
SMARCA4 | 1 | 1.4 | 0.9 |
Total | 110 | - | 100 |
Therapeutic Agent (Trade Name) | Targets | Overview of Current FDA Approval for Different Entities | Overview of Current EMA Approval for Different Entities | Number of Recommended and Received Cases and Responses |
---|---|---|---|---|
Everolimus monotherapy | mTORC1 | HER2-negative and hormone-receptor-positive advanced breast cancer, pancreatic neuroendocrine tumors, RCC, renal angiomyolipoma, and subependymal giant cell astrocytomas (SEGAs) with tuberous sclerosis complex (TSC) | Breast cancer, RCC, and Neuroendocrine tumors of pancreatic, gastrointestinal, or lung origin | Recommended for 36 patients with strong mTOR expression 7 patients received the therapy: 1 patient achieved stable disease 2 patients died prior to radiological assessment 4 patients experienced progressive disease |
Cetuximab | EGFR | CRC and HNSCC | CRC and HNSCC | Recommended in combination with everolimus for 8 patients with EGFR expression and strong mTOR expression 4 patients received the therapy: 1 patient achieved stable disease 1 patient died prior to radiological assessment 2 patients experienced progressive disease Recommended in combination with temsirolimus for and applied in 2 patients with head and neck squamous cell carcinomas with EGFR expression and strong mTOR expression: 1 patient died prior to radiological assessment 1 patient experienced progressive disease |
Exemestane | Aromatase | Estrogen-receptor-positive breast cancer | Estrogen-receptor positive breast cancer | Recommended in combination with everolimus for 21 patients with estrogen expression and strong mTOR expression 8 patients received the therapy: 2 patients discontinued therapy due to toxicity 1 patient died prior to radiological assessment 5 patients experienced progressive disease |
Sorafenib | PDGFR, RAF kinase, VEGFR, | HCC, RCC, and thyroid carcinoma | HCC, RCC, and thyroid carcinoma | Recommended in combination with everolimus for and applied in 1 patient with KIT expression, PDGFRA expression, and strong mTOR expression who experienced progressive disease |
Imatinib | ABL1, BCR, KIT, and PDGFR | Ph+ CML, KIT+ GIST, MDS/MPD associated with PDGFR, and Ph+ ALL | Ph+ CML, KIT+ GIST, MDS/MPD associated with PDGFR, and Ph+ ALL | Recommended in combination with everolimus for 1 patient with KIT mutation, PDGFRA expression, and strong mTOR expression |
Temsirolimus monotherapy | mTOR | RCC | MCL and RCC | Recommended for 2 patients with strong mTOR expression 1 patient received the therapy and achieved stable disease |
Number, Gender, Tumor entity | Detected Mutations, Gene Fusions, FISH | Score in Immunohistochemistry | Applied Targeted Therapy | Age (Years) at Molecular Profiling | TTF (Months) | Therapeutic Response | Cause of Therapy Termination |
---|---|---|---|---|---|---|---|
1 Male Fibrolamellar hepatocellular carcinoma | AKT1 | EGFR = 300, PTEN = 220, mTOR = 270 | Everolimus + cetuximab | 29.7 | 94.7 | SD | n.a.* (Therapy ongoing) |
2 Female Carotid paraganglioma | TP53 | mTOR = 200 | Temsirolimus monotherapy | 51.5 | 63.7 | SD | n.a.* (Therapy ongoing) |
3 Male Sigmoid colon cancer | NRAS: c.C181A PTEN: c.T302G | EGFR = 220, mTOR = 100 | Everolimus monotherapy | 74.7 | 9.1 | SD | PD |
4 Female Cancer of unknown primary | AKT1: c.G49A SMAD4: c.G1051C | EGFR = 150, MET = 2, mTOR = 110 | Everolimus monotherapy | 77.4 | 4.4 | PD | PD |
5 Female Endometrial cancer | PTEN: c.G389A | EGFR = 20, ER (Allred score) = 3, PR (Allred score) = 9 mTOR = 270 | Everolimus + exemestane | 61.3 | 4.4 | PD | PD |
6 Female Biliary tract cancer | BRAF: c.G1397T | MET = 2, mTOR = 100, ER (Allred score) = 3, PR (Allred score) = 6 | Everolimus + exemestane | 65.5 | 4.2 | PD | PD |
7 Female Ovarian cancer | TP53: c.759_767del CHD1: c.1467_1487del | EGFR = 80, ER (Allred score) = 12, PR (Allred score) = 3, PTEN = 140, mTOR = 125 | Everolimus + exemestane | 53.7 | 4.0 | PD | PD |
8 Male T-cell lymphoblastic lymphoma | PTEN: c.696del, heterozygous deletion detected by FISH | mTOR = 80 | Everolimus monotherapy | 21.6 | 3.3 | PD | PD |
9 Male Tongue cancer | PTEN: c.C301T, heterozygous PTEN deletion detected by FISH | EGFR = 210, mTOR = 150, MET = 1 | Temsirolimus + cetuximab | 59.4 | 3.2 | PD | PD |
10 Female Cervical cancer | TP53: c.G1015T, | EGFR = 100, ER (Allred score) = 8, PR (Allred score) = 8, mTOR = 70 | Everolimus + exemestane | 38.9 | 2.9 | PD | PD |
11 Female Sigmoid colon cancer | TP53: c.G626A, heterozygous PTEN deletion detected by FISH | EGFR = 110, MET = 1, mTOR = 240 | Everolimus + cetuximab | 19.3 | 2.8 | PD | PD |
12 Male Prostate cancer | No mutations detected, heterozygous PTEN deletion detected by FISH | mTOR = 110 | Everolimus monotherapy | 69.7 | 2.8 | PD | PD |
13 Male Rectal cancer | TP53: c.G743GA KRAS: c.A182AT, heterozygous PTEN deletion detected by FISH | EGFR = 50, mTOR = 65 | Everolimus monotherapy | 56.9 | 2.7 | PD | PD |
14 Male Biliary tract cancer | BRAF: c.G1397A CDKN2A: c.G256A | EGFR = 250, MET = 3, mTOR = 200 | Everolimus + cetuximab | 60.8 | 2.6 | PD | PD |
15 Female Ovarian cancer | TP53: c.G800A | EGFR = 20, mTOR = 300, ER (Allred score) = 8, PR (Allred score) = 6 | Everolimus + exemestane | 64.7 | 2.6 | n.a. | Died |
16 Female Ovarian cancer | TP53: c.815T > A | EGFR = 10, PTEN = 80, mTOR = 180, ER (Allred score) = 7, PR (Allred score) = 5 | Everolimus + exemestane | 61.8 | 2.1 | PD | PD |
17 Female Ovarian cancer | TP53: c.681dup, heterozygous deletion detected by FISH | MET = 2, PTEN = 140 | Everolimus monotherapy | 71.9 | 1.8 | n.a. | Died |
18 Male Prostate cancer | IDH1: c.C394T, | EGFR = 260, MET = 1, mTOR = 240 | Everolimus + cetuximab | 59.7 | 1.6 | n.a. | Died |
19 Male T-cell lymphoblastic lymphoma | No mutations detected | KIT = 3, mTOR = 200 | Everolimus + sorafenib | 21.4 | 1.4 | PD | PD |
20 Female Gastric neuroendocrine tumor | No mutations detected | mTOR = 180 | Everolimus monotherapy | 74.7 | 1.2 | n.a. | Died |
21 Female Ovarian cancer | TP53: c.C742T, TBL1XR1–PIK3CA gene fusion, ESR1–CCDC170 gene fusion | EGFR = 230, ER (Allred score) = 7, PTEN = 70, mTOR = 110 | Everolimus + exemestane | 77.9 | 1.1 | n.a. | Toxicity |
22 Female Ovarian cancer | PIK3R1: c.C1106T, TP53: c.A1789T, NF1: c.C8070A | ER (Allred score) = 7, PTEN = 150, mTOR = 180 | Everolimus + exemestane | 55.2 | 1.0 | n.a. | Toxicity |
23 Male Squamous cell carcinoma of the retromolar trigone | CTNNB1: c.C172T, heterozygous deletion detected by FISH | EGFR = 240, mTOR = 50 | Temsirolimus + cetuximab | 64.3 | 0.4 | n.a. | Died |
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Taghizadeh, H.; Maj-Hes, A.; Prager, G.W.; Müllauer, L.; Mader, R.M. Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors. Cancers 2022, 14, 1936. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081936
Taghizadeh H, Maj-Hes A, Prager GW, Müllauer L, Mader RM. Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors. Cancers. 2022; 14(8):1936. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081936
Chicago/Turabian StyleTaghizadeh, Hossein, Agnieszka Maj-Hes, Gerald W. Prager, Leonhard Müllauer, and Robert M. Mader. 2022. "Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors" Cancers 14, no. 8: 1936. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081936